L-dopa is the major drug used for Parkinson's disease (PD). One of the problems with l-dopa is the loss of efficacy following long-term administration. Both l-dopa and its product, dopamine (DA), are avid methyl acceptors. In turn, they deplete S-adenosylmethionine (SAM), the biological methyl donor. This interaction may be the key to understand the loss of efficacy of L-dopa. The hypothesis proposed is that l-dopa induces changes that destroy L-dopa its self as well as DA. The high levels of L- dopa therapy, create great demands for the methyl groups. To satisfy this demand the body increases the activities of methionine adenosyl transferase (MAT), the enzyme that produces SAM, and catechol-O-methyltransferase (COMT), the enzyme that transfers the methyl group of SAM to L-dopa and DA. More SAM will be produced and the metabolism of l-dopa and DA will be increased. It means that the DA levels usually attained at the neuronal synapse during early therapy with L-dopa will no longer be attainable after its long-term use. The aims of this project are to how: (1) that L-dopa depletes SAM; (2) that the enzymes MAT and COMT are increased during chronic application of L-dopa, and (3) that L-dopa metabolism is increased following the induction of MAT and COMT. Various chemical agents will be tested for their ability to block the induction of the enzymes and the increased metabolism of l- dopa. At present, there is no study examining the role of both MAT and COMT in regard to the loss of efficacy of L-dopa, so this proposal may be a novel approach. Better management strategies for the long-term use of L- dopa may eventually develop from this study.